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PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments
Isabelle Tanjoni1, Colin Walsh, Sean Uryu
1Department of Reproductive Medicine, Moores Cancer Center, University of California-San Diego, La Jolla, CA USA.
Abstract:
Tumor cells can grow in an anchorage-independent manner. This is mediated in part through survival signals that bypass normal growth restraints controlled by integrin cell surface receptors. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase that associates with integrins and modulates various cellular processes including growth, survival, and migration. As increased FAK expression and tyrosine phosphorylation are associated with tumor progression, inhibitors of FAK are being tested for anti-tumor effects. Here, we analyze PND-1186, a substituted pyridine reversible inhibitor of FAK activity with a 50% inhibitory concentration (IC50) of 1.5 nM in vitro. PND-1186 has an IC50 of ~100 nM in breast carcinoma cells as determined by anti-phospho-specific immunoblotting to FAK Tyr-397. PND-1186 did not alter c‑Src or p130Cas tyrosine phosphorylation in adherent cells, yet functioned to restrain cell movement. Notably, 1.0 µM PND-1186 (>5-fold above IC50) had limited effects on cell proliferation. However, under non-adherent conditions as spheroids and as colonies in soft agar, 0.1 µM PND-1186 blocked FAK and p130Cas tyrosine phosphorylation, promoted caspase-3 activation, and triggered cell apoptosis. PND-1186 inhibited 4T1 breast carcinoma subcutaneous tumor growth correlated with elevated tumor cell apoptosis and caspase 3 activation. Addition of PND-1186 to the drinking water of mice was well tolerated and inhibited ascites- and peritoneal membrane-associated ovarian carcinoma tumor growth associated with the inhibition of FAK Tyr-397 phosphorylation. Our results with low-level PND-1186 treatment support the conclusion that FAK activity selectively promotes tumor cell survival in three-dimensional environments.
Insights
Focal adhesion kinase (FAK) inhibitors like PND-1186 show promise in blocking tumor cell survival and growth, particularly in non-adherent conditions. This targeted approach inhibits FAK activity, leading to apoptosis and reduced tumor progression in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tumor cells exhibit anchorage-independent growth, often by activating survival signals that bypass normal restraints.
- Focal adhesion kinase (FAK) is a key protein-tyrosine kinase involved in cell growth, survival, and migration, associating with integrins.
- Elevated FAK expression and phosphorylation correlate with tumor progression, making FAK inhibitors a therapeutic target.
Purpose of the Study:
- To investigate the anti-tumor effects of PND-1186, a novel FAK inhibitor.
- To determine the efficacy of PND-1186 in preclinical models of breast and ovarian carcinoma.
- To elucidate the mechanism by which PND-1186 affects tumor cell survival and growth.
Main Methods:
- In vitro analysis of PND-1186's inhibitory concentration (IC50) against FAK activity.
- Assessment of PND-1186's effects on FAK and p130Cas phosphorylation in adherent and non-adherent cancer cells.
- Evaluation of PND-1186's impact on cell proliferation, apoptosis (caspase-3 activation), and tumor growth in mouse models.
Main Results:
- PND-1186 demonstrated potent FAK inhibition in vitro (1.5 nM IC50) and in breast carcinoma cells (~100 nM IC50).
- Low-level PND-1186 treatment selectively inhibited FAK and p130Cas phosphorylation, induced apoptosis, and suppressed tumor growth in non-adherent and in vivo models.
- PND-1186 was well-tolerated in mice and effectively inhibited ovarian carcinoma growth, highlighting its therapeutic potential.
Conclusions:
- FAK activity is crucial for tumor cell survival in three-dimensional environments.
- PND-1186 is a potent FAK inhibitor that selectively targets tumor cell survival, offering a promising therapeutic strategy for various cancers.
- Targeting FAK with inhibitors like PND-1186 represents a viable approach to combatting tumor progression and metastasis.
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